•The Immune SystemThe Immune System•The Immune SystemThe Immune System

• The body’s defenseThe body’s defense• 1. Nonspecific1. Nonspecific• 2. Specific 2. Specific • Cell mediatedCell mediated• Antibody mediatedAntibody mediated

• The body’s defenseThe body’s defense• 1. Nonspecific1. Nonspecific• 2. Specific 2. Specific • Cell mediatedCell mediated• Antibody mediatedAntibody mediated

• Three cooperative lines of defense have evolved to counter these threats.• Two of these are nonspecific - that is, they

do not distinguish one infectious agent from another.

• Three cooperative lines of defense have evolved to counter these threats.• Two of these are nonspecific - that is, they

do not distinguish one infectious agent from another.

•Nonspecific defenses•Nonspecific defenses

• “Nonspecific” = don’t have to recognize an invader to fight it

• Skin: physical barrier• Sweat glands: chemical defense

• Mucous membranes:• Line body openings- physical barrier• Secretions:

• Antimicrobial proteins present in secretions• Mucous traps particles• Acid in stomach-destroy most except hept.A

• “Nonspecific” = don’t have to recognize an invader to fight it

• Skin: physical barrier• Sweat glands: chemical defense

• Mucous membranes:• Line body openings- physical barrier• Secretions:

• Antimicrobial proteins present in secretions• Mucous traps particles• Acid in stomach-destroy most except hept.A

• Besides being a physical barrier, the skin and mucous membranes chemically destroy pathogens.• Secretions from oil and sweat glands give

the skin a pH ranging from 3 to 5, acidic enough to kill most microbes.

• Growth is also inhibited by saliva, tears, and mucous secretions that continually bathe the exposed epithelium.

• All these secretions contain antimicrobial proteins.• One of these, the enzyme lysozyme, digests

the cell walls of many bacteria, destroying them.

• Besides being a physical barrier, the skin and mucous membranes chemically destroy pathogens.• Secretions from oil and sweat glands give

the skin a pH ranging from 3 to 5, acidic enough to kill most microbes.

• Growth is also inhibited by saliva, tears, and mucous secretions that continually bathe the exposed epithelium.

• All these secretions contain antimicrobial proteins.• One of these, the enzyme lysozyme, digests

the cell walls of many bacteria, destroying them.

•2ND LINE-Internal•2ND LINE-Internal

• Microbes that penetrate the first line of defense face the second line of defense, which depends mainly on phagocytosis, the ingestion of invading organisms by certain types of white cells.

• Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins.

• Microbes that penetrate the first line of defense face the second line of defense, which depends mainly on phagocytosis, the ingestion of invading organisms by certain types of white cells.

• Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins.

• Second line of defense cells function like roaming patrols

• 1. Nonspecific defenses of chemicals and cells-Stimulated by

cytokinnins• 2. Act rapidly with infection• 3. Employ negative test that cannot

be foiled by copycat foreign cells

• Second line of defense cells function like roaming patrols

• 1. Nonspecific defenses of chemicals and cells-Stimulated by

cytokinnins• 2. Act rapidly with infection• 3. Employ negative test that cannot

be foiled by copycat foreign cells

• 4. All cells possess major histocompatibility complex (MHC) proteins

• 5. Different in each individual. Distinguish self from non self. Due to MHC proteins-before birth• 1. MHC 1-nucleated cells-body cells• 2. MHC II- Nucleated cells-macrophages-B cells-

some t cells• a. 50 alleles-20 genes• b. In autoimmune diseases defensive cells attack body's

own tissues• c.Autoimmune diseases like arthritis have inflammation

without infection

• 4. All cells possess major histocompatibility complex (MHC) proteins

• 5. Different in each individual. Distinguish self from non self. Due to MHC proteins-before birth• 1. MHC 1-nucleated cells-body cells• 2. MHC II- Nucleated cells-macrophages-B cells-

some t cells• a. 50 alleles-20 genes• b. In autoimmune diseases defensive cells attack body's

own tissues• c.Autoimmune diseases like arthritis have inflammation

without infection

•Major Histocompatibility Complex•Major Histocompatibility Complex• The basis of “self”• Genes for cell surface glycoproteins• In humans: human leukocyte antigens (HLA)

• ENORMOUS variation (polymorphic)• 2 Types:

• Class 1: found on all nucleated cells• Class 2 : found on macrophages, B cells, CD4 T cells

• The basis of “self”• Genes for cell surface glycoproteins• In humans: human leukocyte antigens (HLA)

• ENORMOUS variation (polymorphic)• 2 Types:

• Class 1: found on all nucleated cells• Class 2 : found on macrophages, B cells, CD4 T cells

•Phagocytic and Natural Killer Cells•Phagocytic and Natural Killer Cells• Neutrophils:• Most abundant WBC’s • Chemotaxic• Engulf invaders, then self-destruct

• Monocytes:• Less abundant, but more effective than

neutrophils• Form macrophages• Reach pathogen with pseudopodia• Engulf pathogen, fuse it with a lysosome

• Kill pathogen with toxic oxygen or enzymes

• Neutrophils:• Most abundant WBC’s • Chemotaxic• Engulf invaders, then self-destruct

• Monocytes:• Less abundant, but more effective than

neutrophils• Form macrophages• Reach pathogen with pseudopodia• Engulf pathogen, fuse it with a lysosome

• Kill pathogen with toxic oxygen or enzymes

•More WBC’s•More WBC’s

• Eosinophils:• Fight large invaders (ex: parasites)

• Natural Killer (NK) cells: destroy “self” cells infected with viruses, cancer cells

• Eosinophils:• Fight large invaders (ex: parasites)

• Natural Killer (NK) cells: destroy “self” cells infected with viruses, cancer cells

•The Inflammatory Response•The Inflammatory Response• Histamine is released by circulating leucocytes called

basophils and by mast cells in connective tissue.• Histamine triggers both dilation and increased

permeability of nearby capillaries.• Also discharge prostaglandins and other substances that

promote blood flow to the site of injury.

• Greater clotting capacity, faster repair• Initiated by chemical signals • From microbe- Chemotactic factor • From damaged ‘self’ cells (ex: histamine)

• Chemokines from damaged cells attract phagocytes

• Pus = dead phagocytes + fluids• Extreme = septic shock

• Histamine is released by circulating leucocytes called basophils and by mast cells in connective tissue.

• Histamine triggers both dilation and increased permeability of nearby capillaries.

• Also discharge prostaglandins and other substances that promote blood flow to the site of injury.

• Greater clotting capacity, faster repair• Initiated by chemical signals • From microbe- Chemotactic factor • From damaged ‘self’ cells (ex: histamine)

• Chemokines from damaged cells attract phagocytes

• Pus = dead phagocytes + fluids• Extreme = septic shock

•The Complement System•The Complement System

• Antimicrobial proteins• ~ 20 serum proteins• Function: microbe lysis

• Antimicrobial proteins• ~ 20 serum proteins• Function: microbe lysis

• Another set of proteins that provide nonspecific defenses are the interferons, which are secreted by virus-infected cells.– While they do not seem to benefit the infected

cell, these proteins diffuse to neighboring cells and induce them to produce other chemicals that inhibit viral reproduction.

– Interferon limits cell-to-cell spread of viruses, helping to control viral infection.

– Because they are nonspecific, interferons produced in response to one virus may confer short-term resistance to unrelated viruses.

– One type of interferon activates phagocytes.

• Another set of proteins that provide nonspecific defenses are the interferons, which are secreted by virus-infected cells.– While they do not seem to benefit the infected

cell, these proteins diffuse to neighboring cells and induce them to produce other chemicals that inhibit viral reproduction.

– Interferon limits cell-to-cell spread of viruses, helping to control viral infection.

– Because they are nonspecific, interferons produced in response to one virus may confer short-term resistance to unrelated viruses.

– One type of interferon activates phagocytes.

•Temperature Response•Temperature Response

• Pyrogens• Ex: Interleukin-1

• Detected in blood by hypothalamus -- raise in body temp

• How it works:• Speeds cellular reactions• Stimulates phagocytosis• Stimulates liver/spleen to store Fe

• Endotherms - may regulate behaviorally

• Pyrogens• Ex: Interleukin-1

• Detected in blood by hypothalamus -- raise in body temp

• How it works:• Speeds cellular reactions• Stimulates phagocytosis• Stimulates liver/spleen to store Fe

• Endotherms - may regulate behaviorally

•Immunity terms•Immunity terms

• Humoral vs Cell mediated• Acquired/active vs Passive• Lymphocytes: T and B cells, specific• Antigen: Foreign molecule (from pathogens,

pollen, transplanted tissue, etc.)• Antibodies: made by B cells, specific• Antigen receptors: on membranes of T & B

cells• B cells: membrane antibodies• T cells: similar, but never secreted

• Humoral vs Cell mediated• Acquired/active vs Passive• Lymphocytes: T and B cells, specific• Antigen: Foreign molecule (from pathogens,

pollen, transplanted tissue, etc.)• Antibodies: made by B cells, specific• Antigen receptors: on membranes of T & B

cells• B cells: membrane antibodies• T cells: similar, but never secreted

•T cells•T cells

• TI = inducer• TC = cytotoxic • killers

• TH = helpers• Activate others

• TS = suppressor• Causes B cells to ignore antigens

• TI = inducer• TC = cytotoxic • killers

• TH = helpers• Activate others

• TS = suppressor• Causes B cells to ignore antigens

•Antigen presentation•Antigen presentation

• Antigen binds to MHC within cell• MHC molecules bring proteins to

surface

• Antigen binds to MHC within cell• MHC molecules bring proteins to

surface

•Cell mediated response•Cell mediated response

• TC cells kill cancer cells, viral infected cells

• All cells have class 1 MHCs (all susceptible to viral infection)• Class 1 MHC captures viral protein• MHC + antigen move to cell surface• Present to T cytotoxic cell

• Enhanced by CD8

• Active killer cell

• TC cells kill cancer cells, viral infected cells

• All cells have class 1 MHCs (all susceptible to viral infection)• Class 1 MHC captures viral protein• MHC + antigen move to cell surface• Present to T cytotoxic cell

• Enhanced by CD8

• Active killer cell

•Mechanism•Mechanism

• T cytotoxic cell releases perforin• Forms pores in membrane of

target cell• Cell lyses, pathogen inside is

exposed to circulating antibodies

• T cytotoxic cell moves on to other cells infected w/ same pathogen

• T cytotoxic cell releases perforin• Forms pores in membrane of

target cell• Cell lyses, pathogen inside is

exposed to circulating antibodies

• T cytotoxic cell moves on to other cells infected w/ same pathogen

•Antibody mediated immunity•Antibody mediated immunity• Aka Humoral immunity, B cells

activated, antibody production• Ex: macrophage engulfs a bacterium• Class 2 MHC picks up bacterial peptide• MHC + antigen move to cell surface• Presents to T helper cell/releases Il-1

• Enhanced by CD4 receptor on T helper cell

• T cell proliferates• Activated T helper cells: secrete cytokines to

stimulate other lymphocytes

• Aka Humoral immunity, B cells activated, antibody production• Ex: macrophage engulfs a bacterium• Class 2 MHC picks up bacterial peptide• MHC + antigen move to cell surface• Presents to T helper cell/releases Il-1

• Enhanced by CD4 receptor on T helper cell

• T cell proliferates• Activated T helper cells: secrete cytokines to

stimulate other lymphocytes

•Humoral response in detail•Humoral response in detail• B cell activation by IL-2, proliferate into

plasma and memory cells• Plasma cells: secrete antibodies• Memory cells: long-lived

• Some antigens are T-independent • Bind to membrane antibodies on B cells• Plasma cells made w/ out signal from T cells

• B cell activation by IL-2, proliferate into plasma and memory cells• Plasma cells: secrete antibodies• Memory cells: long-lived

• Some antigens are T-independent • Bind to membrane antibodies on B cells• Plasma cells made w/ out signal from T cells

•Structure of antibodies•Structure of antibodies• Globular protein, in plasma, • aka: immunoglobulins (Igs)• Structure: 4 chains: 2 heavy, 2 light• Constant region• Variable region• Epitope: part of the antigen where antibody

binds• 5 classes

• Made in vitro• Polyclonal: made from many B cell clones

• Work on different epitopes of the same antigen

• Monoclonal: made from one B cell clone• All work at the same epitope of the same antigen

• Globular protein, in plasma, • aka: immunoglobulins (Igs)• Structure: 4 chains: 2 heavy, 2 light• Constant region• Variable region• Epitope: part of the antigen where antibody

binds• 5 classes

• Made in vitro• Polyclonal: made from many B cell clones

• Work on different epitopes of the same antigen

• Monoclonal: made from one B cell clone• All work at the same epitope of the same antigen

•How antibodies work•How antibodies work• Neutralization:• Block antigen activity

• Opsonization:• Enhance macrophage

attachment/phagocytosis

• Agglutination:• Clumping

• Complement fixation: • can be activated by antibodies or by

pathogens• Antibodies attach to antigens• Complement proteins activate, cause lysis

• Neutralization:• Block antigen activity

• Opsonization:• Enhance macrophage

attachment/phagocytosis

• Agglutination:• Clumping

• Complement fixation: • can be activated by antibodies or by

pathogens• Antibodies attach to antigens• Complement proteins activate, cause lysis

•Active vs. Passive Immunity•Active vs. Passive Immunity• Active immunity: your own response• Natural: from infection• Artificial: from vaccinations

• Passive: antibodies from another individual• Ex: across placenta, through breast milk• Ex: antivenoms,Rhogam

• Rhogam: injection given to Rh- mothers after birth of Rh+ child.

• Destroy fetal cells before her immune system responds to them, develops antibodies

• Anti Rh antibodies are class IgG - can cross placenta

• Active immunity: your own response• Natural: from infection• Artificial: from vaccinations

• Passive: antibodies from another individual• Ex: across placenta, through breast milk• Ex: antivenoms,Rhogam

• Rhogam: injection given to Rh- mothers after birth of Rh+ child.

• Destroy fetal cells before her immune system responds to them, develops antibodies

• Anti Rh antibodies are class IgG - can cross placenta

•Tissue transplantation•Tissue transplantation

• Blood types: ‘A’ and ‘B’ antigens• T-independent humoral response• Antibodies don’t cross the placenta

• Organ transplants• Rejection due to MHCs that are too

dissimilar• Suppress immune system to decrease

rejection• Bone marrow: graft rejection

• Blood types: ‘A’ and ‘B’ antigens• T-independent humoral response• Antibodies don’t cross the placenta

• Organ transplants• Rejection due to MHCs that are too

dissimilar• Suppress immune system to decrease

rejection• Bone marrow: graft rejection

•Overactive/under active Immune Systems•Overactive/under active Immune Systems• Allergies: antigen induces inflammatory

response• Histamine released from mast cells

• Anaphylactic shock: severe allergic reaction, may cause death (due to BP)• Epinephrine may counteract

• Autoimmune diseases: immune system attacks self tissue• Lupus, rheumatoid arthritis, MS, type 1

diabetes

• Allergies: antigen induces inflammatory response• Histamine released from mast cells

• Anaphylactic shock: severe allergic reaction, may cause death (due to BP)• Epinephrine may counteract

• Autoimmune diseases: immune system attacks self tissue• Lupus, rheumatoid arthritis, MS, type 1

diabetes

•Under active Immune System•Under active Immune System• Immunodeficiency diseases: • Severe combine immunodeficiency (SCID)

• Genetic, need marrow transplant• May treat w/ gene therapy

• Hodgkin’s: damages lymphatic system

• AIDS• Susceptible to opportunistic infections• Caused by HIV, 2 strains• Infect CD4 cells: requires CD4 receptor and co-

receptor• Implications for treatment:

• Chemokines bind to coreceptor - may block entry• Defective CD4 receptors prevent infection

• Immunodeficiency diseases: • Severe combine immunodeficiency (SCID)

• Genetic, need marrow transplant• May treat w/ gene therapy

• Hodgkin’s: damages lymphatic system

• AIDS• Susceptible to opportunistic infections• Caused by HIV, 2 strains• Infect CD4 cells: requires CD4 receptor and co-

receptor• Implications for treatment:

• Chemokines bind to coreceptor - may block entry• Defective CD4 receptors prevent infection

•More on AIDS•More on AIDS

• High mutation rate• Test is actually for HIV antibodies• T cell count indicates disease

progression• Drugs only slow the progression,

are very expensive• 30-40 million (?) world wide cases• 70% in sub-saharan Africa

• High mutation rate• Test is actually for HIV antibodies• T cell count indicates disease

progression• Drugs only slow the progression,

are very expensive• 30-40 million (?) world wide cases• 70% in sub-saharan Africa